The proposed research is to investigate the intracellular mechanisms involved in negative inotropic action of anesthetics using the functionally skinned fiber preparations. Substantial evidence suggests some of the mechanisms involved are in the contractile process. Results from our studies suggest that certain anesthetics can affect (1) the Ca ion-activated tension development, and (2) the Ca2 ion uptake by and release from the sarcoplasmic reticulum (SR) in the functionally skinned fibers. We plan to investigate further the effects of other anesthetics (isoflurane, methoxyflurane, nitrous oxide, cyclopropane, barbiturates, ketamine and morphine) on the Ca2 ion-activated tension development in the functionally skinned myocardial cells by studying their effect on (1) the Ca2 ion activation of the contractile proteins by measuring the changes in (CA2 ion)-tension relationship, and (2) the Ca2 ion uptake and release from the SR by measuring the changes in tension transients induced by caffeine, Ca2 ion, Cl minus and Na ion. We have already demonstrated that halothane and enflurane inhibit Ca2 ion uptake by the SR in the functionally skinned myocardial cells. By measuring the quantity of 45Ca2 ion loaded or released from the SR in the functionally skinned soleus muscle fibers, we will further investigate whether the anesthetic effect is on Ca2 ion transport or permeability changes in the SR membranes resulting in low Ca2 ion uptake. The dose-response relationship of the anesthetics will be determined on the above parameters of the contractile process. The interaction between the anesthetic and pharmacological agents will also be studied. The data will help elucidate the mechanism of anesthetic-induced myocardial depression and will provide us with a better understanding of how anesthetics alter cardiac function in humans which will permit a more rational use of these anesthetics and drugs.